High serum carbohydrate antigen-125 (CA-125) level predicts poor ...

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Carbohydrate antigen-125 (CA-125) was established as a prognostic marker in cancer, especially in ovarian carcinoma. Many recent studies have also reported ...
Int J Hematol (2012) 96:58–64 DOI 10.1007/s12185-012-1102-1

ORIGINAL ARTICLE

High serum carbohydrate antigen-125 (CA-125) level predicts poor outcome in patients with follicular lymphoma independently of the FLIPI score Vı´t Procha´zka • Edgar Faber • Ludeˇk Raida Zuzana Kapita´nˇova´ • Katerˇina Langova´ • Karel Indra´k • Toma´sˇ Papajı´k



Received: 12 December 2011 / Revised: 7 May 2012 / Accepted: 11 May 2012 / Published online: 26 May 2012 Ó The Japanese Society of Hematology 2012

Abstract Carbohydrate antigen-125 (CA-125) was established as a prognostic marker in cancer, especially in ovarian carcinoma. Many recent studies have also reported on the prognostic significance of CA-125 in patients with different types of lymphoma, but only a few studies have been carried out in patients treated with rituximab or high-dose therapy. The prognostic impact of CA-125 on a large cohort of patients with follicular lymphoma (FL) has not been studied. This study analyzed the prognostic significance of CA-125 levels in 116 prospectively enrolled patients with previously untreated FL. It showed that the CA-125 level at the time of treatment initiation correlates with the clinical stage, number of involved nodal areas, bulky disease, hemoglobin level, beta-2 microglobulin level, and lactate dehydrogenase level. Patients with CA-125 [35 U/mL had significantly shorter progression-free (p \ 0.001) and overall (p = 0.025) survival rates. Cox regression analysis identified high CA-125 levels as a prognostic factor for overall (HR 3.04, p = 0.05) and progression-free (HR 3.55, p \ 0.001) survival rates independent of FLIPI score variables. CA-125 levels may help to refine risk assessment in the modern immunotherapy era. Keywords Follicular lymphoma  Chemotherapy  Autologous transplantation  CA-125  Prognosis

V. Procha´zka  E. Faber  L. Raida  Z. Kapita´nˇova´  K. Indra´k  T. Papajı´k (&) Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky´ University Olomouc, I. P. Pavlova 6, 77520 Olomouc, Czech Republic e-mail: [email protected] K. Langova´ Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky´ University Olomouc, Olomouc, Czech Republic

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Introduction Follicular lymphoma (FL) accounts for about 20–30 % of all non-Hodgkin’s lymphomas (NHL) in Western Europe and the USA [1]. In Central Europe (the Czech Republic), the incidence is about 19 %, as seen from the Czech Lymphoma Study Group registry data [2]. Although FL is a clinically and biologically heterogeneous disease, the outcome for patients has dramatically improved over the last decade, especially after targeted therapy with monoclonal antibodies was introduced [3]. For years, risk assessment in patients with FL was based on five independent prognostic parameters contained in the Follicular Lymphoma International Prognostic Index (FLIPI). The index is composed of the following variables: age over 60 years, lactate dehydrogenase level above the upper limit of normal, involvement of more than 4 lymph node groups, hemoglobin (Hb) level of less than 120 g/L and advanced stage of the disease (Ann Arbor classification). The FLIPI is used to evenly distribute patients into three different prognostic groups: low, intermediate and high risk [4]. The predictive value of the FLIPI was confirmed by a large number of prospective studies of both untreated [5, 6] and relapsed patients [7]. Although the FLIPI score is used globally as the gold standard, its historical and methodological limitations must be considered. First, the FLIPI was created in the pre-rituximab era; that means, at the time when only few patients were treated with intensive (high-dose) anthracyclinebased chemotherapy and autologous stem cell transplantation. In these patient groups, the predictive value of the index may be limited. Another problem is the FLIPI endpoint, i.e., overall survival (OS). It is possible that if progression-free survival (PFS) was assessed, the score would include other variables as well. Moreover, from a current

CA-125 in follicular lymphoma

perspective, PFS is a much more practical tool for comparing the individual treatment modalities in indolent lymphoma. With better (longer) survival of FL patients, studies with OS as the endpoint would take a rather long time. Clinical heterogeneity and implementation of novel treatment approaches including risk-adapted therapy justify a need for novel specific prognostic factors for FL patients. One of promising prognostic tools in the assessment of FL patients is measuring carbohydrate antigen-125 (CA125) levels. CA-125 is a 220-kDa glycoprotein produced by cells derived from the celomic epithelium of the female genital tract, the mucosa of the colon and stomach, and mesothelial cells of the serous membranes [8]. Its antigenic determinant was identified by the OC125 antibody produced by the OVCA433 carcinogenic ovarian epithelium cell line [9]. This soluble factor was established as a prognostic marker in cancer, especially in ovarian and gastric carcinoma [10, 11]. Although lymphoma cells do not secrete CA-125, several investigators have reported serum elevations of CA-125 in up to 40 % of patients with NHL, particularly when peritoneal, pleural or pericardial effusions are present [12]. Many past studies also reported prognostic influence of CA-125 in patients with different types of lymphoma [13–15], but only a few studies were carried out in patients treated with rituximab or high-dose therapy [16–18]. Some studies found the prognostic impact of CA-125 controversial. For example, Bonnet and colleagues published a study of prognostic factors in 99 patients with advanced-stage Hodgkin’s and non-Hodgkin’s lymphoma. The OS and PFS were not different in patients with normal or elevated CA-125 levels. Multivariate analyses showed significantly inferior OS and PFS rates in patients with high beta-2 microglobulin (B2M) but no influence of CA-125 [19]. On the other hand, a recently published large epidemiological survey showed that in most studies, CA-125 is a predictor for not only PFS, but also OS [20]. The prognostic impact of CA-125 on a large cohort of FL patients has not been established yet. This study analyzed the prognostic significance of CA-125 levels in 116 prospectively enrolled patients previously untreated FL. Serum CA-125 levels were correlated with baseline clinical and laboratory parameters and the overall outcome.

Patients and methods Laboratory analyses were determined on fresh samples collected on the same day at diagnosis. The serum concentration of CA-125 was quantified with an electrochemiluminescence immunoassay (ECLIA) using the

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Elecsys CA-125 kit (Roche Diagnostics) and the Modular E170 autoanalyser with a measuring range of 0.6–5000 UI/mL. A cutoff was set at a standard reference value of 35 U/mL as proposed by Bast [9]. Patient study group A total of 116 prospectively enrolled FL patients with lymphoma grades I–IIIa treated at the Department of Hemato-Oncology, University Hospital Olomouc between January 1995 and March 2010 were analyzed. In all patients, the diagnosis of NHL was based on readings of biopsy specimens and confirmed by a university center hematopathologist according to the WHO Classification of tumors of haematopoietic and lymphoid tissues. The analyzed group comprised 34 males and 82 females with a median age at diagnosis of 54 years (range 31–79 years). Most of the patients (75 %) had advanced disease stage according to the Ann Arbor classification system. The disease stages were as follows: stage I in 11, stage II in 18, stage III in 19 and stage IV in 68 of the 116 patients. Lymphoma grade was determined in 95 of the 116 patients (82 %), with the grades being as follows: grade 1 (42 patients), grade 2 (43 patients) and grade 3A (10 patients). More than a half of the patients had bone marrow involvement (58 of 113 analyzed, 51.3 %) and a tumor mass larger than 7 cm (58 of 111, 52.3 %). Systemic symptoms were present in 40 of 116 patients (34.5 %). The FLIPI scores were as follows: low in 35 (30.2 %), intermediate in 33 (28.4 %) and high in 48 (41.4 %) patients. Anemia with Hb levels below 120 g/L was present in 22 patients (19 %). B2M levels were elevated above 3 mg/L in 51 of 115 (44.3 %) patients. Mean CA-125 serum level was 56.9 ± 102.6 UI/mL and was elevated in 42 patients (36.2 %). This study was approved by the institutional independent ethics committee and performed in accordance with the Declaration of Helsinki. Treatment Thirteen patients (11 %) did not fulfill the GELF criteria for systemic treatment initiation [21]. These patients—all with a limited disease stage—were observed (watch and wait policy) or treated with rituximab monotherapy or with local involved-field radiotherapy. One hundred and three patients (89 %) were treated with chemotherapy. Sixty-two patients (60.2 %) were able to receive therapy with lymphoma risk-appropriate intensity, whereas 60 patients (39.8 %) were treated with standard CHOP-like therapy irrespective of the disease risk. The frontline treatment of the 62 suitable patients was stratified according to the commonly used risk factors

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V. Procha´zka et al.

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(FLIPI, B2M and serum thymidine kinase levels, bulky disease) and with regard to age and comorbidities into 3 treatment groups: (1) patients with FLIPI 0-1 treated with (R)-CHOP (25 patients, 39 %); (2) patients under 60 (65) years of age with intermediate-risk disease (FLIPI 2) indicated for an intensive protocol (ProMACE-CytaBOM or sequential chemotherapy) (12 patients, 19 %); and (3) patients under 60 (65) years with high-risk disease (FLIPI C 3) with additional risk factors treated with intensive chemotherapy plus autologous stem cell transplantation (BEAM) (27 patients 43 %). Rituximab was added to frontline chemotherapy in 82 (80 %) of the treated patients. Maintenance treatment after frontline therapy was indicated in 45 (44 %) of the chemotherapy-treated patients. Thirty-four of them received rituximab (375 mg/m2 every 3 months for 24 months), 8 patients were treated with interferon alpha (3MU three times per week for 24 months) and 3 patients received consolidation with ibritumomab-tiuxetan. Chemotherapy protocols CHOP and ProMACE-CytaBOM protocols were administered as previously published [22, 23]. The sequential chemotherapy protocol consisted of 3 cycles of CHOEP21-like regimen (PACEBO), 1 cycle of an ifosfamide and methotrexate-based regimen (IVAM) and a priming regimen with high-dose cytosine arabinoside (HAM). The PACEBO regimen was administered as follows: doxorubicin 40 mg/m2 intravenously, day 1; cyclophosphamide 850 mg/m2 intravenously, day 1; etoposide 200 mg/m2 intravenously, day 1; bleomycin 10 mg/m2 intravenously, day 8; vincristine 1.4 mg/m2 (maximum 2.0 mg) intravenously, day 8; and prednisone 40 mg/m2 orally, days 1–14. The IVAM regimen consisted of ifosfamide 1500 mg/m2 intravenously, days 1–5; etoposide 150 mg/m2 intravenously, days 1–3; cytosine arabinoside 100 mg/m2 intravenously, days 1–3; methotrexate 3 g/m2 intravenously, day 5; mesna prophylaxis 1,200 mg intravenously, days 1–5; and leucovorin rescue 25 mg/m2 intravenously, from day 6/7 until the plasma methotrexate level was below 0.05 lmol/L. The HAM regimen was administered as follows: cytosine arabinoside 2 g/m2 twice daily intravenously, days 1 and 2; mitoxantrone 10 mg/m2, days 2 and 3 [24]. Stem cell mobilization was performed with 12 lg/kg of filgrastim given subcutaneously twice daily. The BEAM 200 conditioning regimen dosage was standard as previously published [25]. Treatment response The treatment responses—complete response (CR), unconfirmed complete response (CRu), partial response

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(PR), stable disease (SD) and progressive disease (PD)— were defined according to the International Workshop NHL Response Criteria published by Cheson et al. [26]. Statistical analysis The data were analyzed using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL). The OS was defined as the time from the diagnosis to the date of last follow-up examination (censored) or the date of death (event) from any cause. The PFS was defined as the date of first treatment to the date of documented disease progression or death (event) or the date of last follow-up examination (censored). The Kaplan–Meier method was used to calculate survival probabilities. The log-rank test was used to compare differences in survival times between patient subgroups. The significance level was set at p = 0.05; twotailed tests were used in all calculations. The relationship between CA-125 levels (normal or elevated) and the standard prognostic factors was analyzed using the Chisquared or Mann–Whitney U test for qualitative or quantitative variables, respectively. Univariate analysis was performed using logistic regression for each variable separately, multivariate analysis was performed using the Cox proportional hazards model fitted to assess effect on OS and PFS of serum CA-125 and other characteristics.

Results Univariate analysis was performed to compare patient populations with normal and elevated CA-125 (Table 1). Elevated CA-125 was associated with advanced clinical stage (p \ 0.001), number of involved lymph nodes (p = 0.03), presence of tumor bulk (p \ 0.001), elevated LDH level (p \ 0.001), Hb level below 120 g/L (p = 0.003), elevated B2M level (p \ 0.001) and higher FLIPI score (p \ 0.001). No association was found between the CA-125 level and lymphoma grade (p = 0.21). Analysis of treatment response and survival Treatment response was assessable in 110 of 116 (94.8 %) patients. CR or CRu was achieved in 94 (85.5 %), PR in 13 (11.8 %) and SD or PD in 3 (2.7 %) of the patients. Those with high CA-125 levels above 35 U/mL had a lower probability of CR achievement than patients with CA-125 levels below the limit (73.2 vs. 87.9 %, p = 0.05). After a median follow-up of 60 months (range 12–209 months), the OS of all patients reached 92.7 % (95 % CI 0.88–0.98) at 5 years. The PFS at 5 years reached 65.3 % (95 % CI 0.56–0.75). The 5-year OS of

CA-125 in follicular lymphoma

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Table 1 Correlation between CA-125 levels and clinical features of 116 patients with follicular lymphoma CA-125 B35 IU/L

CA-125 [35 IU/L

[60

20

12

B60

54

30

Male

21

13

Female

53

29

Characteristics

p value

Age (years) 0.86

Gender 0.08

Clinical stage Limited (I/II)

24

5

Advanced (III/IV)

50

37

Present

22

18

Absent

52

24

\0.001

Systemic symptoms 0.15

No. of involved lymph nodes B4

38

13

[4

30

25

Present

26

32

Absent

45

8

Below the limit

54

19

Above the limit

20

23

\120 g/L

8

14

C120 g/L

66

28

\3 mg/L

54

10

C3 mg/L

31

20

0.03

Fig. 1 Overall survival curves. Patients with CA-125 level B35 U/mL (solid line), patients with CA-125 level [35 U/mL (broken line), p = 0.025

Tumor bulk \0.001

LDH level 0.003

Hb level 0.003

B2M level \0.001

FLIPI score Low

30

5

Intermediate

24

9

High

20

28

1

30

12

2

28

15

3a

7

3

\0.001

FL grade 0.21

patients with elevated CA-125 levels was 79.1 % (95 % CI 0.65–0.93), as compared to 92.3 % in patients with CA-125 below the limit (95 % CI 0.86–0.99, p = 0.025) (Fig. 1). The 5-year PFS of patients with elevated CA-125 level was 42.9 % (95 % CI 0.30–0.59), as compared to 79.2 % (95 % CI 0.68–0.90, p \ 0.001) in patients with CA-125 below the limit (Fig. 2). During the observation period, lymphoma relapsed in 31 patients (median time to relapse 25.1 months; range 5.5–76.2 months) and 14 patients died (5 of them in CR).

Fig. 2 Progression-free survival curves. Patients with CA-125 level B35 U/mL (solid line), patients with CA-125 level [35 U/mL (broken line), p \ 0.001

Patients with high CA-125 relapsed early. All but one relapses (events) were observed within the first 39 months (1 late relapse in 60 months) and about a half of the relapses occurred within the first 23 months. The pattern of relapses in the low CA-125 group was different. Half of the patients relapsed within the first 3 years (34.2 months) and the patients relapsed slowly but continuously. The last relapse was observed more than 1 year later (at 76 months) than in the high CA-125 group. Subanalysis of the 82 patients treated with rituximabcontaining regimen showed superior 5-year PFS in patients with CA-125 level \35 U/mL (85.9 %, 95 % CI 0.75–0.97) compared to those with CA-125[35 U/mL (54.5 %, 95 % CI 0.36–0.73, p = 0.004) (Fig. 3). The OS survival curves were not different in patients with normal or elevated CA-125 levels (91.2 vs. 83.0 %, p = 0.44) (data not shown).

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V. Procha´zka et al.

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Table 2 Univariate Cox models for progression-free survival Variable

Exp (B)

p value

95 % CI

Age (above 60)

1.80

0.09

0.91–3.56

Gender

0.87

0.72

0.41–1.86

Clinical stage (advanced)

1.48

0.39

0.61–3.55

No. of nodal areas involved (more than 4)

1.43

0.32

0.71–2.87

Hb level (below 120 g/L)

1.10

0.81

0.50–2.43

LDH level (above the limit)

1.43

0.32

0.71–2.87

B2M level (above 3 mg/L)

2.77

0.004

1.38–5.54

CA-125 level (above 35 U/mL)

3.54

\0.001

1.81–6.94

Table 3 Univariate Cox models for overall survival Fig. 3 Progression-free survival curves of 82 patients treated with rituximab. Patients with CA-125 level B35 U/mL (solid line), patients with CA-125 level [35 U/mL (broken line), p = 0.004

Variable

Exp (B)

p value

95 % CI

Age (above 60)

6.35

\0.001

2.10–19.1

Gender

1.06

0.92

0.33–3.38

No. of nodal areas involved (more than 4)

1.1

0.86

0.37–3.28

Hb level (below 120 g/L)

1.54

0.47

0.48–4.95

LDH level (above the limit)

1.57

0.40

0.55–4.48

B2M level (above 3 mg/L)

4.77

0.02

1.33–17.1

CA-125 level (above 35 U/mL)

3.26

0.034

1.09–9.73

Clinical stage (advanced)

Fig. 4 Progression-free survival curves of 27 patients treated with high-dose therapy and autologous stem cell transplantation. Patients with CA-125 level B35 U/mL (solid line), patients with CA-125 level [35 U/mL (broken line), p = 0.01

Similarly, patients with very high-risk FL treated with up-front high-dose therapy with autologous stem cell support have different outcome regarding CA-125 levels. In the group with CA-125 \35 U/mL, only 1 event was observed in 15 patients (7 %); in the elevated CA-125 group, 5 out of 12 patients (42 %) relapsed or progressed. The 5-year PFS was significantly different (100 vs. 50 %, p = 0.01) (Fig. 4). The OS was not different in patients with normal or elevated CA-125 levels (100 vs. 90 %, p = 0.24) (data not shown). Univariate and multivariate analyses Univariate analysis of the five FLIPI prognostic factors identified only age above 60 as a predictor for OS (HR

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6.35, 95 % CI 2.10–19.1, p \ 0.001). None of the FLIPIrelated parameters were found to be predictors for PFS (Tables 2 and 3). Besides the FLIPI factors, B2M (HR 2.77, 95 % CI 1.38–5.54, p = 0.004) and CA-125 (HR 3.54, 95 % CI 1.81–6.94, p \ 0.001) levels were identified as significant predictors for PFS (Table 2). The above serological parameters also predict the OS: B2M (HR 4.77, 95 % CI 1.33–17.1, p = 0.02) and CA-125 (HR 3.26, 95 % CI 1.09–9.73, p = 0.034) (Table 3). The effects of multiple factors on PFS and OS were analyzed using logistic regression. The following variables were evaluated: age, sex, serum LDH level, bulky disease, clinical stage, number of involved nodal areas, bone marrow involvement, Hb and CA-125 levels. Two prognostic factors independently predict OS: age above 60 years (HR 5.49, 95 % CI 1.83–17.36, p = 0.003) and CA-125 [35 U/mL (HR 3.79, 95 % CI 0.99–9.32, p = 0.05). Only one factor was found predictive for PFS: CA-125 (HR 3.55, 95 % CI 1.76–7.15, p \ 0.001). Inclusion of B2M into multivariate analysis with the above-mentioned covariates led to substitution of CA-125 by B2M in the prediction of OS. In this complex model, B2M (HR 3.78, 95 % CI 1.04–13.82, p = 0.044) and age (HR 5.02, 95 % CI

CA-125 in follicular lymphoma

1.61–15.64, p = 0.005) were identified as independent predictors. In multivariate analysis set for PFS, CA-125 remains the sole independent predictor (HR 3.65, 95 % CI 1.81–7.35, p \ 0.001). When FLIPI scores were included as individual prognostic variables in multivariate Cox regression analysis, CA-125 was confirmed as an independent prognostic value (HR 3.54, 95 % CI 1.81–6.93, p = 0.0002). In multivariate analysis of the patients treated with rituximab, five FLIPI variables (age, serum LDH level, clinical stage, Hb level, number of involved nodal areas) and the CA-125 level were analyzed. The only factor found to be predictive for the OS was age above 60 (HR 5.86, 95 % CI 1.39–24.65, p = 0.016). Similarly, only one factor was predictive for PFS—the LDH level (HR 4.24, 95 % CI 1.67–10.12, p = 0.002).

Discussion Our study found pretreatment serum CA-125 levels to be a predictor of survival, independent on the FLIPI variables. The role of CA-125 seems to be particularly in prediction of early disease relapses. Patients with CA-125 B35 U/mL have much more favorable outcome, with the 5-year PFS by about 36 % higher than those with high CA-125. The effect on the PFS was also confirmed in patients treated with rituximab with 31 % difference in 5 years (54.5 vs 85.9 %). Remarkably, this simple soluble factor has also potential to predict the outcome after high-dose therapy. The interval to disease progression was statistically different between the CA-125 groups, in spite of the limited number of analyzed cases. On the other hand, the role of conventional prognostic factors implemented into the FLIPI score was only limited. Apart from age above 60, none of the FLIPI-related parameters were found to be significant predictors in either univariate or multivariate analyses. The CA-125 level strongly correlates with well-known unfavorable nonFLIPI-related parameters such as bulky disease and B2M levels. Therefore, the CA-125 level probably reflects disease characteristics other than FLIPI parameters [27]. This fact may help to explain its independent predictive power. The patient population enrolled in the study shared many unfavorable features: almost a half of them had highrisk FLIPI scores, more than a half had bulky disease and almost three quarters of the patients had advanced clinical stage. Those were reasons for application of more intensive treatment strategies including high-dose therapy and autologous stem cell transplantation. Risk-adapted intensive therapy can probably overcome the negative prognostic impact of conventional FLIPI risk factors. The prognostic value of serum CA-125 assessment was confirmed in several clinical trials in the rituximab era.

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First, Gawad and colleagues from Cairo University analyzed the prognostic role of CA-125 in patients with diffuse large B cell lymphoma (DLBCL). With a cutoff level of 20 U/mL, they found CA-125 to correlate with stage, tumor bulk, involvement of more than 1 extranodal site, and presence of effusion. Elevated CA-125 and LDH levels were found to predict decreased survival [16]. Second, Gutie´rrez and coworkers analyzed a novel sexspecific reference value in 42 patients with DLBCL treated with R-CHOP chemotherapy. The authors found a correlation between high serum CA-125 pretreatment levels and clinical stage, remission quality and survival. The use of a sex/age-adjusted reference value for CA-125 increased the sensitivity to identify those patients with elevated CA-125 levels truly related to DLBCL activity [18]. The largest study was performed in China, where Gui et al. analyzed prognostic factors in 415 NHL patients. Multiple Cox regression analysis showed that the IPI score complemented by the additional serum markers B2M and CA-125 was a better prognostic factor of OS and EFS rates than LDH alone [17]. The only recent study which found no prognostic role of CA-125 was published by Bonnet and coworkers in 2007. This study analyzed the outcome of 99 patients with both Hodgkin’s disease and various types of NHL. In spite of the fact that CA-125 levels correlated with poor performance status, the presence of B symptoms, advanced clinical stage, abdominal, bone marrow or mediastinal involvement, presence of effusions, high aaIPI, low Hb levels and high CRP, LDH or B2M levels, no association was found between CA125 levels and the outcome [19]. Uncertainty regarding the utility of CA-125 was partially resolved by large epidemiological analysis published by Rohit P. Ojha [20] from the University of North Texas Health Science Center, USA. This systematic review indicated that results derived from analyses of CA-125 as a marker for advanced stage and mortality in NHL are generally concordant. Finally, in FL patients treated with rituximab and risk modern treatment approaches, pretreatment CA-125 level assessment represents a cheap and valuable prognostic marker. This parameter may serve as a useful factor complementary to the conventional FLIPI. Acknowledgments Supported by grants from the Czech Ministry of Education (MSM 6198959205) and Faculty of Medicine and Dentistry, Palacky´ University Olomouc (LF-2012-007). Conflict of interest

The authors declare no conflict of interests.

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